Olanzapine I is an orally active, potent, antipsychotic agent. ##STR1##
It is commercially available as Zyprexa.RTM. from Eli Lilly Co. The antipsychotic effect of olanzapine is ascribed by the literature to blocking of the dopamine D.sub.2 receptor and to 5-HT antagonism.
One of the main serum metabolites of olanzapine is 2-hydroxymethylolanzapine II, formed by oxidation of the methyl group at the 2-position of the thiophene ring. The chemical name of II is 4-(1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepin-2-methanol and hereinafter is referred to as 2-hydroxymethylolanzapine. ##STR2##
Formation of 2-hydroxymethylolanzapine occurs in the liver through the enzymes of the P450 system. 2-Hydroxymethylolanzapine is formed by cytochrome P450 2D6 (CYP2D6). CYP2D6 is polymorphically expressed in the human population. The mutant allele constitutes the recessive trait. Homozygous carriers of the mutation completely lack CYP2D6 and are referred to as poor metabolizers; persons homozygous and heterozygous for the "normal" allele are extensive metabolizers. In addition to problems arising from variability in dosage regimens, the clinical use of CYP2D6-metabolized drugs and of CYP2D6 inhibitors, which includes a variety of antiarrhythmic agents, beta-adrenoceptor blockers and tricyclic antidepressants, in conjunction with olanzapine, may inhibit olanzapine metabolism.
It is therefore desirable to find a compound with the advantages of olanzapine which would provide a more predictable dosage regimen in the patient population and that would decrease the chances for drug-drug interaction.